SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice

The 2007 Consensus Statement for Standard of Care in Spinal Muscular Atrophy (SMA) notes that patients suffer from gastroesophageal reflux, constipation and delayed gastric emptying. We used twomousemodels of SMA to determinewhether functional GI complications are a direct consequence of or are secondary to survivalmotor neuron (Smn) deficiency. Our results show that despite normal activity levels and food and water intake, Smn deficiency caused constipation, delayed gastric emptying, slow intestinal transit and reduced colonic motility without gross anatomical or histopathological abnormalities. These changes indicate alterations to the intrinsic neural control of gut functionsmediated by the enteric nervous system (ENS). Indeed, Smn deficiency led to disrupted ENS signaling to the smoothmuscle of the colon but did not cause enteric neuron loss. High-frequencyelectricalfield stimulation (EFS) of distal colon segmentsproducedup to a 10-fold greater contractile response in Smn deficient tissues. EFS responses were not corrected by the addition of a neuronal nitric oxide synthase inhibitor indicating that the increased contractility was due to hyperexcitability and not disinhibition of the circuitry. The GI symptoms observed in mice are similar to those reported in SMA patients. Together these data suggest that ENS cells are susceptible to Smn deficiency and may underlie the patient GI symptoms.